title: The inside-out amyloid hypothesis and synapse pathology in Alzheimer's disease.
abstract: Cumulative evidence in brains and cultured neurons of Alzheimer's disease (AD) transgenic mouse models, as well as in human postmortem AD brains, highlights that age-related increases in β-amyloid peptide (Aβ), particularly in endosomes near synapses, are involved in early synapse dysfunction. Our immunoelectron microscopy and high-resolution immunofluorescence microscopy studies show that this early subcellular Aβ accumulation leads to progressive Aβ aggregation and pathology, particularly within dystrophic neurites and synapses. These studies confirm that neuritic/synaptic Aβ accumulation is the nidus of plaque formation. Aβ-dependent synapse pathology in AD models is modulated by synaptic activity and is plaque independent. The amyloid precursor protein (APP) is normally transported down neurites and appears to be preferentially processed to Aβ at synapses. Synapses are sites of early Aβ accumulation and aberrant tau phosphorylation in AD, which alter the synaptic composition at early stages of the disease. Elucidating the normal role of APP, and potentially of Aβ, at synapses should provide important insights into the mechanism(s) of Aβ-induced synapse dysfunction in AD and how to therapeutically mitigate these dysfunctions.
authors.affiliation: Experimental Dementia Research Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Gunnar K
authors.initials: GK
authors.lastname: Gouras
authors.forename: Katarina
authors.initials: K
authors.lastname: Willén
authors.forename: Mathilde
authors.initials: M
authors.lastname: Faideau
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor